My career goal is to be an independent investigator in the neurobiology and treatment of late life depression (LLD) with a focus on understanding the relationship between depression and cognitive impairment (CI) to inform the development of treatments aimed at prevention of cognitive decline in LLD. Thus, this Mentored Patient-Oriented Research Career Development Award (K23) builds upon my background in glucose metabolism in affective disorders and my training as a geriatric psychiatrist to integrate my interest in the mechanisms underlying CI in LLD as well as the role of medical co-morbidity by focusing on the relationship between insulin resistance (IR), brain vascular disease and CI. The overarching hypothesis is that IR represents an early, measurable and modifiable mechanism that links LLD to CI and that the link between IR and CI will be stronger in LLD than in non-depressed individuals. In accordance with my career goals, the career development plan will focus on training in: 1) clinical research methodology including testing longitudinal models, and 2) the neurobiology of LLD with an emphasis on endocrinology and metabolism and the relationship to brain vascular disease and CI. The host institution, the Johns Hopkins University School of Medicine is an ideal setting to meet these objectives. There are strong clinical and academic programs in geriatric psychiatry and neuropsychiatry, geriatric medicine, endocrinology and metabolism, neuropsychology, and neuroimaging. The primary mentor, Dr. Constantine Lyketsos (Clinical Research Methodology) is a geriatric neuropsychiatrist who has made major scientific contributions to epidemiological and treatment studies of neuropsychiatric symptoms in late life and the relationship to cognitive decline. The co-mentor, Dr Gwenn Smith (Neurobiology of LLD) is a neuropsychologist who has focused on the development and applications of molecular imaging methods in late life neuropsychiatric disorders, including LLD. I have developed a productive working relationship with my mentors and together, we have developed the clinical and research infrastructure for LLD. The research plan will focus on measuring IR in LLD and evaluating the relationship to CI and brain vascular disease. The specific aims of the research plan are: 1) To compare IR in the LLD group to a demographically matched control group, and 2) To evaluate the association between IR, brain vascular disease, and CI in the LLD versus controls. The hypotheses to be tested are: 1) the LLD group will have higher mean IR versus the control group; and 2) IR will be correlated with CI in LLD, and that this correlation will be stronger in LLD than in the control group after controlling for brain vascular disease (via white matter hyperintensities (WMH) on brain magnetic resonance imaging), and known cognitive (age, education, and APOE4 status) as well as vascular risk factors (hypertension, dyslipidemia) for CI. We will recruit 40 non-diabetic individuals with a current major depressive episode (onset of current episode after age 60) and 40 non-diabetic, non-depressed, demographically matched controls to undergo an oral glucose tolerance test (to measure IR), neuropsychological testing and a structural brain magnetic resonance imaging scan (to measure WMHs). At the conclusion of the K award, I will have assembled a well-characterized cohort of individuals with LLD (as well as the ability to expand the cohort) who could be followed longitudinally to evaluate the role of IR and brain vascular disease for the development of cognitive decline. The understanding obtained in the proposed study will inform the development of an intervention study to evaluate whether treating IR will lead to acute improvements in cognition as well as lessen the progression of brain vascular disease and CI in LLD. PUBLIC HEALTH RELEVANCE: Late life depression is a significant public health problem as it is associated with a dramatic increase in the rate of completed suicide, with greater mortality in the medically ill elderly and increased risk of developing dementia. Even though there are effective antidepressant agents available, many patients are still refractory to treatment and demonstrate persistent cognitive impairment and cognitive decline, despite mood symptom improvement. The proposed training and research plan will focus on understanding the role of insulin resistance and brain vascular disease in cognitive impairment in depression, which would inform the development of prevention and intervention strategies.